(P 384) SYSTEMATIC LITERATURE AND CLINICAL TRIAL REVIEW SHOWS TARGETABLE KINASE FUSIONS ARE COMMON IN PEDIATRIC, ADOLESCENT, AND YOUNG ADULT SOFT TISSUE SARCOMAS BUT CLINICAL TRIAL OPPORTUNITIES REMAIN RARE

Objective: Oncogenic tyrosine kinase fusions (TKFs) have been reported in pediatric, adolescent, and young adult (AYA) soft tissue sarcomas (STS). Clinical trials such as Larotrectinib for NTRK fusions show high response rates to molecularly targeted therapy (MTT) matched to TKFs in pediatric and AYA STSs. TKFs occur across a broad age range of STSs, so they fall into distinct research and care silos. As a result, data on the relationship between TKFs and clinical features (i.e. diagnosis and stage) is distributed across many studies, and information about response and resistance to MTT is presented in different study types. To address the knowledge gaps resulting from fragmented data, we conducted a systematic review of TKFs reported in pediatric and AYA STSs. We also assessed the availability of clinical trials for pediatric and AYA cancer patients with TKFs.

Methods: A systematic literature search was conducted on PubMed, restricting the publication date to 10 years (2013-2022), during which tumor genomic profiling became more accessible. Search terms included relevant terms for diagnosis, age, and gene names including gene MeSH Terms for BRAF, RAF1, NTRK1-3, ALK, FGFR1-4, MET, RET, and ROS1. Large pediatric sequencing studies including STS patients were also reviewed. Papers were included for abstraction if they reported at least one patient < 30 years old with a TKF-positive STS identified by sequencing or other methods. Data abstracted included report type (case report/series, large sequencing study, molecular pathology methods report, clinical trial study), TKF gene and partner, and diagnosis mapped to ICDOv3.2 codes. Diagnoses occurring in >2 patients were categorized and those in ≤2 were combined in a “Sarcoma, Other” category. When available, additional information for each patient was recorded, including fusion breakpoints, age, stage (local, regional, or metastasis), MTT received, response, and trial enrollment. Clinicaltrials.gov was queried for active or completed interventional trials in the U.S. assessing relevant MTTs in cancer patients.

Results: Our search identified 130 studies (89 case reports/series and 21 pediatric sequencing studies) reporting 401 patients with TKF-positive STSs. TKFs occurred in 22 distinct diagnoses based on ICDOv3.2. Approximately 87% (n=348) of diagnoses were Sarcoma, NOS (8800/3; n=43), spindle cell sarcoma (8801/3; n=55), infantile fibrosarcoma (IFS; 8814/3; n=96), or myofibroblastic tumor, NOS (IMT; 8825/1; n=154). NTRK1-3 were the most common genes involved in TKFs followed, in order of frequency, by ALK, ROS1, BRAF, RET, RAF1, FGFR1-4, and MET. The most common fusion diagnosis pair was ETV6::NTRK3 in IFS (n=66) and TFG::ROS1 in IMT (n=32). Of 60 patients ≥18 years who received MTT, only 17 (28%) were enrolled in a clinical trial. As of Jan 9, 2023, there were 563 trials involving MTTs for TKFs most relevant to the pediatric population. These studies included 47 inhibitors of which only 20 are currently FDA-approved. Patients < 18 years were only eligible for 15% (n=84) of trials (36 completed recruitment and 48 active, recruiting, or not yet recruiting). RET (48%; 10/21) and NTRK (38%; 15/40) inhibitors had the highest percent of trials enrolling patients < 18 years while ERK (6%; 5/79) and MET (2%; 1/41) inhibitors had the least. Notably, there were 173 pediatric and AYA STS patients with an ALK or ROS1 fusion with 73% of patients being < 18 years at diagnosis and only eligible for 24% of ALK or ROS1 inhibitor trials.

Conclusion: To our knowledge, this is the first systematic review of TKFs in pediatric and AYA STSs. While STSs are a heterogeneous group of diseases with distinct histologies, we observe a significant overlap of TKFs across diseases demonstrating a broad need for relevant therapies in these patients. We also observe a discordance between the percentage of pediatric and AYA patients < 18 years old with actionable TKFs and available trials, particularly evident in the ALK and ROS1 TKF-positive patient population.